Field-Effect Transistor-Based Biosensors and a Portable Device for Personal Healthcare

Chen, Pei-Chi; Chen, Yen-Wen; Sarangadharan, Indu; Hsu, Chen-Pin; Chen, Chih-Chen;Shiesh, Shu-Chu; Lee, Gwo-Bin; Wang, Yu-Lin

Published in:ECS Journal of Solid State Science and Technology

Published: 01/01/2017

Document Version:Final Published version, also known as Publisher’s PDF, Publisher’s Final version or Version of Record

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Published version (DOI):10.1149/2.0361707jss

Publication details:Chen, P-C., Chen, Y-W., Sarangadharan, I., Hsu, C-P., Chen, C-C., Shiesh, S-C., Lee, G-B., & Wang, Y-L.(2017). Field-Effect Transistor-Based Biosensors and a Portable Device for Personal Healthcare. ECS Journal ofSolid State Science and Technology, 6(7), Q71-Q76. https://doi.org/10.1149/2.0361707jss

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ECS Journal of Solid State Science and Technology, 6 (7) Q71-Q76 (2017) Q71

Field-Effect Transistor-Based Biosensors and a Portable Device forPersonal HealthcarePei-Chi Chen,a Yen-Wen Chen,a,∗ Indu Sarangadharan,a,∗ Chen-Pin Hsu,aChih-Chen Chen,a,b Shu-Chu Shiesh,c Gwo-Bin Lee,a,b,d,z and Yu-Lin Wanga,b,z

aInstitute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu 300, TaiwanbDepartment of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 300, TaiwancDepartment of Medical Laboratory Science and Biotechnology, National Cheng Kung University,Tainan City 701, TaiwandInstitute of Biomedical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan

In this study, miniaturized AlGaN/GaN high electron mobility transistors (HEMTs) were embedded in a plastics substrate andconnected with metal electrodes. The plastic substrates were then engraved as the shape of a micro SD card, followed by cappingcapillary channel for guiding fluids. C-reactive protein (CRP) aptamer were then immobilized on the HEMT for CRP detection. Thesensor chip can be inserted into a micro SD card socket, which is connected to a circuit designed for reading out the electrical signalsof the sensor. The circuit is controlled by an application software in a laptop. A new methodology was developed to directly detectproteins in high ionic strength solution, such as in 1XPBS or serum, avoiding complicated washing process, leading to less automaticsfor sample pre-treatment and simpler system and operation. It turns out that the system can be small, cheap, and user-friendly forlay-persons. CRP is demonstrated to be directly detected in human serum with the new methodology. CRP prepared in 1XPBS issuccessfully detected with this disposable sensor chip and the portable readout device. The result shows that this portable system ispromising in personal healthcare in the future.© The Author(s) 2017. Published by ECS. This is an open access article distributed under the terms of the Creative CommonsAttribution Non-Commercial No Derivatives 4.0 License (CC BY-NC-ND, http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is not changed in anyway and is properly cited. For permission for commercial reuse, please email: oa@electrochem.org. [DOI: 10.1149/2.0361707jss]All rights reserved.

Manuscript received May 9, 2017. Published June 13, 2017.

Medical devices for personal healthcare, homecare, and mobilediagnostics attract a great interest in recent years. Compared to point-of-care (POC) devices, which are usually bench-top instrument, med-ical devices for individuals require low cost, fast response, simpleoperation, small size, low weight, high sensitivity, and quantitativeanalysis.1–4 Field-effect transistor (FET)-based biosensors have beenextensively demonstrated with high sensitivity, fast response, andquantitative analysis.5–8 However, it is challenging to fabricate FET-based biosensors with low cost, small size, and simple operation forlay-persons. A new package technology is needed to carry tiny FETchip so that the cost of the sensor can be low, and in the meantime, theelectrical bias can be applied to the FET and the signals can be trans-mitted to the circuit. In addition to the signal transmission, the packagetechnology for FET-based biosensors has to ensure the good isolationbetween the liquid sample and the electric wire, which requires wellsurface passivation and appropriate design of the microfluidic chan-nel. Considering the simple operation by lay-persons, the microfluidicchannel is much preferred to be fabricated as capillary because it doesnot requires pipettes for transferring liquid samples.9,10 Besides, com-plicated process, such as washing process to remove the un-boundproteins or dilution of protein solution to reduce the ionic strengthfor increasing Debye length for gaining high sensitivity of FET-basedbiosensor,11–13 should be avoided because they will enlarge the wholemeasurement system due to the need of additional automatics. A newmethodology allows FETs to directly detect proteins in high ionicstrength solution, including 1X PBS or human serum, without losingany sensitivity, is plausible for reaching the final goal, easy and simpleoperation by everyone.

In this study, miniaturized FET-based biosensors are embedded inepoxy substrates, with passivation for isolation of metal interconnectsand protein solution. The substrate is engraved as the same size as amicro SD card, which fits into a commercial socket that is connectedto a read out circuit. The electrical measurement is controlled byapplication software in a laptop. CRP in 1X PBS and in human serais detected with this portable device, without any dilution or pre-treatment, demonstrating the efficacy of our new methodology for

∗Electrochemical Society Student Member.zE-mail: ylwang@mx.nthu.edu.tw; gwobin@pme.nthu.edu.tw

direct protein detection in physiological sample. This study shows thatthis integrated technology has been promising for future applicationfor personal healthcare, homecare and mobile diagnostics.

Materials and Methods

Design and fabrication of AlGaN/GaN HEMTs.—The minia-turized AlGaN/GaN HEMT chips are fabricated with a 1 mm2 diearea. The fabrication follows a top down approach starting with theGaN epi-wafer. It consists of a GaN buffer layer (3 μm), AlGaN (26nm), and GaN cap layer (10 nm) deposited using Molecular BeamEpitaxy (MBE) on Si substrate. The epi-wafer is patterned using pho-tolithography and Inductively coupled Plasma (ICP) etching is usedto form mesa isolations to define transistor active area. Cl2/BCl3 gases(35 sccm/35 sccm) are used under ICP power of 300 W and RF bias of120 W at 2 MHz to perform ICP etching. ohmic contacts are formedusing Ti/Al/Ni/Au (200 Å/400 Å/800 Å/1000 Å) metals deposited byelectron beam evaporator, followed by rapid thermal annealing (RTA)at 850◦C in nitrogen environment. Metal interconnects and gate elec-trode of Ti/Au (200 Å/ 1000 Å) is deposited using evaporator. Theschematic diagram and top view image of the AlGaN/GaN HEMT areshown in Figure 1.

Package of AlGaN/GaN HEMT in a plastic substrate.—The 1mm2 GaN HEMT chips are packaged in a thermo-curable plastic sub-strate using a simple technique. The steps involved in the packagingprocess are illustrated in Figure 2. A block of PMMA is patternedusing laser drilling to generate a rectangular PMMA mold of size(13 × 22 mm2). PDMS (Sylgard 184A prepared by mixing the pre-cursor and solidifier) is poured on the PMMA mold and cured at 65◦Cfor 1–2 hours. Post curing, the PDMS mold can be separated fromPMMA and GaN HEMT chips are placed with the top sides stickingto the PDMS mold. Epoxy resin is poured on to the PDMS moldcovering the HEMT chips. It is then cured for 1.5 hours in 125◦C and1 hour in 165◦C. After cooling down to room temperature, the curedepoxy substrate which has been embedded with GaN HEMT chip isreleased from the PDMS mold. Metal interconnects (200 Å Ti/500 ÅAu/500 Å Pt/2000 Å Au) are laid using evaporator. The entire chipis protected using photoresist (Shipley S1818) while laser drilling is

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Q72 ECS Journal of Solid State Science and Technology, 6 (7) Q71-Q76 (2017)

(a) (b)CRP Aptamer

Figure 1. (a) Schematic diagram of AlGaN/GaN HEMTdevice packaged in polymer substrate. (b) Top view of Al-GaN/GaN HEMT depicting the sensing region consistingof gate electrode opening (100 × 120 μm2) and transistorchannel opening (20 × 60 μm2); the distance between thetransistor channel and gate electrode is 65 μm.

carried out to pattern the epoxy substrate to generate microSD cardlayout. Photolithography process is used to make openings on thetransistor and gate electrode regions, 10 × 60 μm2 and 100 × 120μm2 respectively, which form the sensing region of the GaN HEMTdevice.

Design and fabrication of capillary.—A simple microfluidic cap-illary channel is used to flow the test solution in and out of the chip. Thefabrication of capillary microchannel is illustrated in Figure 3. Mul-tiple double side tapes of thickness (0.16 mm) and area (4 × 6 mm2)

are stacked together and laser drilling is performed to pattern a chan-nel. A hydrophilic film with exact dimensions as double side tape islaser drilled to generate an outlet pattern. The stack of double sidetapes and hydrophilic film are allowed to stick together, resulting in1 mm wide channel with a thickness or height of 0.48 mm. The cap-illary is placed on top of the packaged chip such that the 1 mm2 GaNHEMT device is inside the capillary channel. When test solution isbrought in contact with the interface of the packaged chip and thecapillary channel, the liquid is driven inside due to capillary forceand touches the GaN HEMT device. The laser drilled hole on the top

Step2: PDMS fillingand Baking

SMDPPMMA

Step3: PDMS releasing and placing chip

SMDP

repaP

Step5: Epoxy bakingand releasing

yxopE

Step8: Gate opening

Photoresist

Step1: Laser engraving

resaL

AMMP

yxopE

SMDP

Step4: Filling epoxy

Photoresist

Step7: Passivation and Laser cut

resaL

enillateM

yxopE

Step6: Metallization and lift-off

Figure 2. Schematic illustration of steps involved in packaging AlGaN/GaN HEMT devices in epoxy substrate.

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ECS Journal of Solid State Science and Technology, 6 (7) Q71-Q76 (2017) Q73

Patterning hydrophilic film to design outlet

Laser

Hydrophilic film

Hydrophilic film

0.9 mm mm

1 mm

mm84.0

Double side tape

OutletInlet

Sticking hydrophilic film to the top of double side tape

Laser

Double side tape

Patterning double side tape to design channel

Figure 3. Schematic representation of design of capillary microchannel. The hydrophilic film and stack of double side tapes are patterned using laser drill andstuck together to form the capillary microchannel which is then placed on the packaged chip such that AlGaN/GaN HEMT device is positioned inside the capillarychannel.

hydrophilic film serves as the outlet to drive the liquid away from thedevice.

Surface immobilization of aptamer.—CRP specific aptamer ispurchased from Genomics and is thiol modified so that the aptamercan form a self-assembled monolayer on the gold gate electrode open-ing on HEMT device.14 The CRP aptamer has been proved withgood affinity and specificity15,16 A mixture of aptamer and Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) is prepared in TrisEDTA buffer in the final concentration ratio of 1:1000 and incubatedin room temperature for 15–30 minutes in order to reduce the dithiolbond. The solution is then heated to 95◦C to generate free ssDNAstrands and cooled down to room temperature before incubating onthe GaN HEMT device for 24 hours in room temperature. The un-bound aptamers are washed away using 1X PBS before the electricalmeasurement of the chip.

Clinical serum samples.—Clinical samples of human serum withCRP are obtained as per Institutional review Board (IRB) of NationalCheng-Kung University Hospital (NCKUH) with approval (IRB. No.B-ER-21 104-116) and under supervision by National Tsing Hua Uni-versity IRB approval (10405HE014). The concentration of CRP in theclinical samples is determined using laboratory based diagnostic sys-tem as 0.24, 0.34, 0.65, 0.89, 1.09 and 1.18 mg/L. The serum samplesare used for electrical measurement using AlGaN/GaN HEMT with-out any sample pre-treatments such as filtering or dilution.

Electrical measurement of the AlGaN/GaN HEMT biosensors.—The electrical measurements of HEMT devices are performed usingbench-top semiconductor parameter analyzer Agilent B1500A/B1530and a portable sensor measurement unit. B1500 A is used to supply thedrain voltage and B1530 generates the short duration pulse waveformused as the gate bias. The portable sensor measurement unit has mi-crocontroller unit, associated signal acquisition and read out circuitry

and is connected to the laptop for displaying the results, as shown inFigure 5. The software for GUI allows the user to conduct electricalmeasurements in two modes: single and burst. In single mode of op-eration, drain and gate voltages are supplied for a short duration thatcan range from 50 μs to 1 ms. The software displays the drain currentbefore and after gate bias is applied and the resulting current gain.In burst mode of operation, multiple cycles (n = 1 to 100) of singlepulses of drain and gate voltages can be generated, and the operationyields a current gain signal which is the average of the multiple cyclesof electrical measurement.

Results and Discussion

The schematic and top view images of AlGaN/GaN HEMT chipis shown in Figure 1. The distance between the source and drain con-tacts is 30 μm and the opening on the transistor channel is 20 × 60μm2. The gate electrode which is similar to the reference electrode intraditional FET based biosensor is placed at a fixed distance from thetransistor channel and the gate electrode opening of 100 × 120 μm2

is 65 μmaway from the channel area. This sensor design simulatesthe open areas on the gate electrode and channel as two metal elec-trodes at a fixed gap apart, if we ignore the voltage drop in the highlyconductive channel. The solution containing the target is placed onthe device covering the sensing region which is constituted by theopen areas on the gate electrode and channel, as shown in Figure 1a.In this design of FET biosensor the gate electrode assumes greaterinfluence in regulating channel conductivity than the conventionalreference electrode. When voltage is applied to the gate electrode andthe channel is biased by giving a drain-source voltage, the voltagedrops across the solution, creating electrical double layer at the inter-faces in the gate electrode and channel open areas. This constitutesa solution capacitance CS which modulates the channel conductivity,resulting in changes in the transistor drain current. Equation 1 showsthat the applied gate voltage VG is the sum of the voltage dropped

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Q74 ECS Journal of Solid State Science and Technology, 6 (7) Q71-Q76 (2017)

across the solution VS and the transistor dielectric VOX. Assumingthe linear relationship of voltage and capacitance, the voltage dropin the dielectric is modulated by the solution voltage drop and thusthe solution capacitance CS, as shown in Equation 2. If the dielectriccapacitance COX is fixed, the effective VG applied for transistor gatingis a function of the solution capacitance CS. The value of CS increaseswhen the ionic strength of the solution increases. Thus we can get ahigher current gain in solution with higher ionic strength. The solutioncapacitance is also altered when receptor-ligand binding occurs andthis change can modulate the transistor drain current, according toEquation 2. In this way, we can directly detect the binding of receptorand target protein as it induces a change in solution capacitance andthence the drain current, in high ionic strength medium such as 1XPBS and physiological fluids. In this paper, we would like to discussthe design, fabrication and characterization of packaged AlGaN/GaNHEMT chip and demonstrate the working of portable measurementdevice that uses the HEMT chip with the unique sensing methodology.

Vg = �Vs + �Vox [1]

�Vox =1

jωCox

1jωCox

+ 1jωCs

× Vg = Cs

Cox + Cs× Vg [2]

The AlGaN/GaN HEMT chips, after wafer dicing, have an area of1 mm2. We have developed a simple and robust packaging technologythat deploys the HEMT chips in a polymer substrate.17 Figure 2 illus-trates the fabrication steps involved in the packaging technique. FirstlyPMMA is patterned using laser drill to generate a rectangular block ofPMMA with grooves of certain depth. PDMS mold is fabricated fromthe PMMA block on to which devices are placed at pre-determinedpositions and thermo-curable epoxy resin is poured on it. Post curing,the epoxy substrate containing the embedded HEMT chips is releasedfrom the PDMS mold and metal interconnections are deposited. Thewhole packaged chip is laser cut to the layout of microSD card anda commercial microSD card reader can be used to apply bias andread out the sensor transduction signal. The chip is uniquely designedto adhere to the requirements of a personal healthcare device, suchthat the miniaturized sensor chip can be easily mounted on a portabledevice for electrical measurement and can be discarded after use.

While designing a personal healthcare device, one of the mostimportant aspects is that the system has to be user friendly. Whenthe test solution is a biological fluid such as blood, there needs tobe a microfluidic channel to transport the test solution to the sensingregion of the active device.18 We have designed and fabricated a simplecapillary microchannel that pulls the test liquid in via capillary effectand delivers it to the sensing region. The capillary design is illustratedin Figure 3. A hydrophobic film with an opening for outlet is placedand pasted on top of back to back stack of double side tapes whichis patterned using laser drill to form a channel. The arrangement ofdouble side tape and the hydrophilic film is then placed on top of thepackaged chip such that the HEMT device is placed inside the capillarymicrochannel. When a droplet of test solution, < 2 μL is brought incontact with the edge of the microchannel, the liquid is driven indue to the capillary forces and reaches the HEMT chip. This simplecapillary microchannel requires no external actuation, consumes nopower and requires extremely low sample volume. Since the channelis very narrow and short, there is no loss of target proteins induced bystiction due to surface tension.19

Initially, the working of the packaged AlGaN/GaN HEMT chipis validated by conducting electrical measurements using AgilentB1500A/B1530 semiconductor parameter analyzer. A 100 μs dura-tion pulse of 0.5 V is applied as gate voltage to the gate electrode and 2V DC bias is applied to the transistor drain-source. The resulting draincurrent of HEMT device is displayed in Figure 4. At first the deviceis measured in 1X PBS environment. The gate electrode is function-alized by immobilizing target protein specific aptamer (as describedin methods section). When the surface of gate electrode is modifiedby immobilizing the aptamer and while testing in solution under gate

Figure 4. Drain current versus time graph depicting the CRP concentration (inclinical sera) dependent change of drain current, as obtained with the electricalmeasurements performed using Agilent B1500A/B1530.

bias, the drain current shifts to a new baseline, corresponding to thatof aptamer. This is because surface modifications also contribute tothe change in overall solution capacitance20 and the success of recep-tor immobilization can be validated by testing the drain current ofthe HEMT. The target protein used in this study is C-reactive protein(CRP). Figure 4 shows the CRP concentration dependent change indrain current. The samples used for the electrical measurement areclinical serum samples from different patients containing CRP. Asobserved in Figure 4, the sensor’s signal can clearly distinguish thedifferent concentrations of CRP found in human blood serum, even inthe extremely high ionic strength environment.

The details of the portable electrical measurement system are dis-cussed in Figure 5. The AlGaN/GaN HEMT chip packaged in themicroSD card layout can be connected to a commercial microSD cardreader which is mounted on the portable device, as shown in Figure5a. The device can be connected to laptop via USB interface and thesoftware (image shown in Figures 5a and 5e) installed in laptop canbe used to control the electrical measurement parameters, apply biasvoltages and display the measurement results. The electrical mea-surements can be conducted in two modes of operation: single andburst. The input and output signals of single mode of operation areschematically represented in Figure (b) and (c). As the name suggests,in single mode, only a single short duration pulse is applied as gateand drain voltages which results in a drain current signal from thesolution capacitance generated by the bias application. As shown inFigure 5d, in burst mode, multiple cycles of short duration pulses canbe applied which will result in corresponding drain current signalswhich are averaged and the mean value is displayed. From user pointof view, there is very minimal user protocol to be followed and thetest results can be obtained with a single push of a button.

Figure 6 depicts the results of electrical measurements conductedusing the packaged AlGaN/GaN HEMT chip mounted on the portablemeasurement device. Figures 6a and 6b display the drain current ver-sus time graph for the successful immobilization of aptamer and de-tection of CRP in clinical serum samples, respectively. As indicatedin the graph, the change in drain current after gate voltage is turned onis considered as the current gain of the transistor. The current gain canbe plotted against target protein concentration to generate the sensorcalibration curve (as in Figures 6c and 6d). Purified CRP preparedin 1X PBS containing 4% BSA can be used to test for a wider sen-sor dynamic range and analyze the receptor-ligand binding affinityconstants. As depicted in Figure 6c, the sensor’s signal representedas change in current gain with respect to zero concentration of targetCRP, follows one binding site model closely and yields a KD (disso-ciation constant) value of 14 nM, which is consistent with previouslyreported literature and suggests the clinical application of the sen-sor for diagnosing CRP in patients with cardiovascular diseases.15,16

Figure 6d displays the sensor signal versus concentration curve forthe HEMT chip used to test clinical sera containing CRP. The sensorcan achieve very low detection limits and achieve good linearity in

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ECS Journal of Solid State Science and Technology, 6 (7) Q71-Q76 (2017) Q75

Figure 5. (a) The portable measurement device with USB interface to connect to laptop. The software installed in laptop provides GUI to control measurementparameters and display the test results. Inset shows the packaged AlGaN/GaN HEMT chip connected to microSD card reader which is mounted on the portabledevice. (b) Schematic of the pulsed drain and gate voltages applied to the HEMT device, during the single mode of operation. (c) Schematic of the drain currentof HEMT obtained during single mode of operation that allows pulsed drain and gate voltages. (d) Schematic of the pulsed drain and gate voltages applied to theHEMT device, during the burst mode of operation. (e) The software that provides the GUI to control the test parameters through single or burst mode of operation.

Figure 6. Results of electrical measurements of packaged AlGaN/GaN HEMT performed using the portable measurement device. (a) Drain current versus timegraph depicting the change in current for successful aptamer immobilization. (b) Drain current versus time graph depicting the CRP concentration (in clinicalsera) dependent change in current. (c) Change in current gain versus concentration graph for detection of CRP in 1X PBS with 4% BSA. (d) Current gain versusconcentration graph for detection of CRP in clinical sera.

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Q76 ECS Journal of Solid State Science and Technology, 6 (7) Q71-Q76 (2017)

low concentrations of CRP in serum, revealing the high sensitivity ofCRP measurement using the portable device. Figure 4, Figures 6b and6d show results from two different HEMT devices used to test CRPin human serum. These clinical samples are obtained from differentpatients. The blood serum has numerous background proteins of var-ious types21 in addition to the high strength electrolyte composition.However, the results from tests conducted using our HEMT devicesare only dependent on the concentration of the target protein (CRP)concentration, indicating the high specificity of the sensor toward thetarget protein. The attributes of high sensitivity and specificity in test-ing physiological samples such as blood serum is critical for any assayto maintain reliability and reduce variations across individuals.

Conclusions

In summary, we have fabricated a miniaturized AlGaN/GaNHEMT chip, embedded and packaged it in a polymer substrate that canbe connected to a microSD card reader which is mounted on a portableelectrical measurement device interfaced with laptop to display the testresults. The high sensitivity, ease of use and high economic benefitsassociated with our sensor are achieved by the combination of minia-turization of semiconductor devices, facile integration of packagedHEMT chip with the portable measurement device and simple capil-lary microfluidics. The sensor exhibits good linearity of detection forvery low concentrations of target proteins in physiological environ-ment such as clinical serum where there is a high background proteinconcentration and high ionic strength. This method does not requireany additional sample pre-treatments or labeling. We have developeda portable biosensor system that can be used by any individual withno or minimal user protocols at the comfort of their personal space,to monitor and prevent diseases and improve healthcare.

Acknowledgments

This work was partially supported by Ministry of Science & Tech-nology (MOST 104-2221-E-007-142-MY3), National Health Re-search Institutes (NHRI-EX104-10428EI) and National Tsing Hua

University (105N523CE1). We thank the technical support from Na-tional Nano Device Laboratories (NDL) in Hsinchu and the Centerfor Nanotechnology, Materials science, and Microsystems (CNMM)at National Tsing Hua University.

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